POS0327 SPEED OF RESPONSE MATTERS: POST-HOC ANALYSIS OF PATIENTS WITH EARLY SERONEGATIVE RHEUMATOID ARTHRITIS INCLUDED IN THE CARERA TRIAL
Authors: S. Pazmino, R. Westhovens, V. Stouten, D. Bertrand, M. Doumen, J. Joly, E. De Meyst, D. C. Diederik, P. Verschueren
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Seronegative rheumatoid arthritis (RA) patients have been historically considered to have a milder disease course. <h3>Objectives</h3> We aimed to compare the disease course in seronegative and seropositive patients from the Care in early RA (CareRA) trial. <h3>Methods</h3> We used data from the 2-year RCT CareRA and its 3-year observational follow-up, CareRA plus. Patients completing the year 2 visit of CareRA were eligible for participation in CareRA plus, in which patients were evaluated every 6 months till year 5. The CareRA trial included patients early RA (≤1 year) and naïve to disease-modifying anti-rheumatic drugs. Patients were stratified in a low- and high-risk group according to prognostic markers and randomized to one of four different treatment schemes: a) MTX and a step-down glucocorticoid (GC) scheme (COBRA Slim) b) this combination with either sulphasalazine (COBRA Classic) or c) leflunomide (COBRA Avant-Garde) in high-risk patients, and d) MTX without GCs (Tight-Step-Up: TSU) or e) COBRA Slim in low-risk patients. Treating-to-target, steering at low disease activity (≤3.2) measured in 28 joints with C-reactive protein (DAS28CRP) was applied while aiming for remission (&lt;2.6) as final outcome. Differences in demographic, clinical and laboratory variables were tested with Wilcoxon rank or Chi-square. Multiple testing was corrected with Holms-Bonferroni. Survival analysis using Kaplan-Meier and Cox regression compared (a) time to first remission (DAS28CRP&lt;2.6), (b) time to first loss of disease-control (DAS28CRP&gt;3.2) in those reaching remission, and all subsequent losses of disease-control as recurrent events between seropositive (ACPA or RF positive) and seronegative (ACPA and RF negative) patients. Survival curves were compared with log rank. To model recurrent events, an extended Cox model with random effect, including the presence of erosions at baseline, disease duration, gender, current smoking, treatment scheme with or without GCs and DAS28CRP at baseline and week 16 was used. Multiple imputation (m=100) was used to handle missing data. <h3>Results</h3> Of the 379 included patients, 83 (23%) were seronegative while 292 (77%) were seropositive. Seronegative patients had a similar median age (54 vs 53 years, p=0.58), BMI (26.5 vs 25.7 kg/m<sup>2</sup>, p=1.0), presence of erosions (26% vs 25%, p=1.0) and gender distribution (76% vs 68% females, p=1.0), compared to seropositive patients. However, median disease activity was higher in seronegative patients at baseline: DAS28CRP (5.1 vs 4.7, p&lt;0.01), 28 swollen joint count (8 vs 6, p&lt;0.01) and 28 tender joint count (10 vs 7, p&lt;0.001). DAS28CRP remained significantly higher at week 8 (3.0 vs 2.1, p&lt;0.001), but became comparable by year 1 (2.0 for both p=1.0). There was a significant difference in time to first treatment response between seronegative and seropositive patients as depicted in the inverted Kaplan-Meier plot (Figure 1a). Time to first remission was significantly shorter for seropositive (median 4 weeks IQR 4;8) versus seronegative (8 weeks IQR 4:28) patients (p&lt;0.001). When accounting for the treatment, all COBRA schemes with GCs increased the chance of reaching remission by 58% (HR 1.58; 95%CI 1.10-2.27; p&lt;0.05) compared to TSU (Figure 1b). For the time to first and consecutive losses of disease control after remission, one point higher DAS28CRP at week 16 increased the risk of losing disease control by 59% (HR 1.59; 95%CI 1.38-1.82; p&lt;0.0001), serology status was not significantly predictive of loss of response. <h3>Conclusion</h3> In CareRA, seronegative patients, who have been historically considered to have a milder form of the disease, had a higher initial disease activity, longer time to first treatment response and greatly benefited from an initial treatment scheme that included glucocorticoids. Speed of response during the window of opportunity for RA has been highly advocated. Our findings highlight that seronegative RA requires an equally intensive initial treat-to-target therapy as seropositive RA to reap the benefits of the window of opportunity. <h3>Acknowledgements</h3> CareRA was supported by a grant from the Flemish government Agency for Innovation by Science and Technology (IWT) and by grants from the Fund for Scientific Research in Rheumatology (FWRO) and the Academic Foundation of Leuven. <h3>Disclosure of Interests</h3> Sofia Pazmino: None declared, Rene Westhovens: None declared, Veerle Stouten: None declared, Delphine Bertrand: None declared, Michaël Doumen: None declared, Johan Joly: None declared, Elias De Meyst: None declared, De Cock Diederik: None declared, Patrick Verschueren Grant/research support from: Patrick Verschueren holds the Pfizer chair for early rheumatoid arthritis management at the KU Leuven.